The potential advantages of transdermal administration of drugs into systemic body circulation comprise mainly principal restriction of the undesirable influence of the first pass effect based on biotransformation of agent(s) in the liver, decrease of the risk of overdosing and the risk of undesirable side effects of drug(s). Other advantages are noninvasive and continual character of administration and possibility of simple interruption of it when problematic situations arise.
During several past decades, the research effort has been oriented for using transdermal route of drug administration in the form of practically usable pharmaceutical preparations. A series of significant results has been reached in this field and has brought successes in the therapeutic and, consequently, in the commercial area. An extensive outline of this topic can be found in the review by Cleary, G. W.: Transdermal delivery systems: A medical rationale. In: Shah, V. P., Maibach, H. I.; Topical Drug Bioavailability, Bioequivalence and Penetration. Plenum Press, New York, London, 1993. pp. 16-68, and/or in the compendium by Chien, Y. W.: Novel Drug Delivery Systems. 2nd Ed., Marcel Dekker, New York, Basel, Hong Kong, 1992, 797 pp.
Transdermal penetration of drugs as such is principally limited by natural barrier properties of the skin for majority of substances. Therefore various approaches enabling transdermal absorption of agents in a reversible way are used. They include, e.g., occlusion, optimisation of polarity properties of vehicles, iontophoresis, sonophoresis, application of a concept of prodrugs and the use of transdermal absorption enhancers (accelerants or enhancers of skin penetration or permeation). The given problem is dealt in the monography by Walters, K. A., Hadgraft, J.(Eds.): Pharmaceutical Skin Penetration enhancement. Marcel Dekker, New York, Basel, Hong Kong 1993, 440 pp.
Transdermal penetration enhancers are substances, that interact with skin components or with pharmaceutical preparation components or with active agent(s) to increase the permeability of the skin for these agents in a reversible way. Enhancers of transdermal penetration extend possibilities of topical administration of agents with the purpose of systemic as well as local treatment by this route.
Information available on this topic up to 1981 was extensively dealt in the monography by Barry, B. W. Dermatological Formulations. Percuataneous Absorption. Marcel Dekker, New York, Basel, 1983, 408 pp. Newer information dealing with the given field are disposable in the article by Walters, K. A.: Penetration enhancers and their use in transdermal therapeutic systems. In: Hadgraft, J., Guy, R. H. (Eds.): Transdermal Drug Delivery. New York, Marcel Dekker, 1989, pp. 197-246 and/or in an extensive outline by Williams, A. C., Barry, B. W.: Skin absorption enhancers. CRC Crit. Rev. Ther. Drug Carrier Systems, 9 (3,4), 1992, pp. 305-353. A substantial outline comprising patent literature in the field of permeation enhancers since 1992 is given in the work by Santus, G. C., Baker, R. W.: Transdermal enhancer patent literature. J. Control. Rel., 25, 1993, pp. 1-20. Topical information dealing with the problem of skin absorption enhancers are reviewed by Kalbitz, J., Neubert, R., Wohlrab, W.: Modulation der Wirkstoffpenetration in die Haut. Pharmazie 51(9), 1996, pp. 619-637 and/or in the monography by Ranade, V. V., Hollinger, M. A.: Drug Delivery Systems. CRC Press, Boca Raton, 1995, 364 pp.
The use of permeation enhancers or their combinations for transdermal administration of various drug(s) is described in numerous recent patents, such as PCT Int. Appl. WO 9402, 119; PCT Int. Appi. WO 9323,019; PCT Int. Appl.WO 9323,025; Eur. Pat. Appl. EP 569, 338; PCT Int. Appl. 9325, 197; Eur. Pat. Appl. EP 581,587; Eur. Pat. Appl. EP 582,458; Eur. Pat. Appl. EP 680,759; Eur. Pat. Appl. 644,922; PCT Int. Appl. WO 9303,697; PCT Int. Appl. WO 9603,131; PCT Int. Appl. WO 9706,788.
There is a large number of substances interacting with the skin and its stratum corneum. Transdermal penetration enhancers as substances used in pharmaceutical preparations have to meet a set of qualitative criteria; they must not be toxic, they must not irritate, allergize or sensitize the skin and they should be pharmacologically inert at the concentrations required to exert adequate permeation action. Their effect shoud be immediate, predictive and reversible. At the same time they should be easily incorporated into pharmaceutical preparations as well as cosmetically acceptable (addapted from: Barry, B. W.: Dermatological Formulations. Percutaneous Absorption. Marcel Dekker, New York, Basel, 1983, pp. 167-172; Hadgraft, J.: Penetration enhancers in percutaneous absorption. Pharm. Int., 5, 1984, pp. 252-4; Pfister, W. R., Hsieh, D. S. T.: Permeation enhancers compatible with transdermal drug delivery systems. Part I., II. Pharm. Technol. Int., 3 (1) 1991, pp. 32-6, 3 (2), pp.28-32.
It is understandable that no univeral permeation enhancer has not been and probably would not be identified.
Derivatives of .omega.-amino acids, both cyclic and linear, can be included, however, among very promising and recently intensively studied substances exerting enhancing effect on transdermal penetration and permeation. The most significant substance of this group is 1-dodecylazacycloheptan-2-one (laurocapram, Azone.RTM.), patented in 1976 (Rajadhyaksha, V. J., Vieo, M.: U.S. Pat. No. 3,989,815 and U.S. Pat. No. 3,989,916). Some other substances being used for this purpose are aryl-methyl-2-pyrrolidone (U.S. Pat. No. 3,969,516) and, for instance, derivatives of azepanone substituted in various ways (Santus, G. C., Baker, R. W.: J. Control. Release 25, 1993, pp. 1-20). Their disadvantage is that they cannot be easily dispersed in aqueous solutions and their effect is inhibited by the presence of some auxiliary substances commonly used as constituents in topical preparations. For instance, auxiliary substances of the paraffinic carbohydrate type (e.g., petrolatum) can completely inhibit permeation enhancing effect of laurocapram (Stoughton, R. B., McClure, W. O.: Azone.RTM.: A new non-toxic enhancer of cutaneous penetration. Drug. Dev. Ind. Pharm. 9, 1983, pp. 725-744). Within the group of linear derivatives of .omega.-amino acids, esters of lysine (Eur. Pat. Appl. No. 84200822) and/or esters of .epsilon.-aminocaproic acid (CZ Pat. 276300) can be mentioned.
As used herein, the term "transdermal penetration enhancer" refers to the substance(s) applicable in pharmaceutical preparations to increase penetration and permeation of drug(s) topically administered on human or animal skin with the aim of reaching therapeutically effective concentrations of drug(s) and other pharmacologically active agent(s) in deeper layers of the skin and/or adjacent tissues or for reaching effective concentrations of active agent(s) in systemic circulation of a living organism.